For the clinical treatment of acute and chronic severe pain, morphine is utilized as a standard analgesic. Morphine-related derivatives have been synthesized by simplification and introduction of substituents into the morphine structure in order to develop powerful analgesics without side effects (Corbett et al., 2006). Analgesics such as fentanyl and buprenorphine have been consequently derived from morphine. Most of them have μ-receptor agonist profiles and are used clinically. Despite their profound utility in the management of pain, they have undesirable side effects such as constipation, respiratory, depression, and development of dependence. It is known that μ-opioids such as morphine induce not only potent antinociception but also undesired rewarding effects following chronic administration in mice. The activation of dopaminergic systems after systemic administration of a μ-opioid agonist induces development of hyperlocomotion and place preference in mice (Matthes et al., 1999). Inhibitory effects on gastrointestinal transit (IGIT), such as constipation, tend to be a significant problem during administration of a chronic opioid such as morphine. The dose required for morphine's analgesic effect is much higher than that required for its constipating effect; thus, when morphine is used for analgesia, constipation is not a negligible issue (Megens et al., 1998).
The traditional Thai herbal medicine Mitragyna speciosa has long been used in Thailand for its opium- (Burkill, 1935) and coca-like effects and as a replacement for opium (Grewal, 1932; Suwanlert, 1975). The leaves of Mitragyna speciosa have been used, and are effective when taken orally. This medicinal herb contains many indole alkaloids (Takayama 2004). Mitragynine, illustrated below, a main constituent of this plant, is an indole alkaloid and structurally different from morphine, also illustrated below.

Studies have been done on the pharmacological activities of mitragynine (Watanabe et al., 1997; Matsumoto et al., 2005) and related alkaloids (Yamamoto et al., 1999; Takayama et al., 2002; Takayama, 2004; Matsumoto et al., 2006a), which have found that these compounds have agonistic effects on opioid receptors. Recently, studies have been done on the opioid agonistic effects of the constituents of Mitragyna speciosa using in vitro assays. Among them, 7-hydroxymitragynine, illustrated below, which has a hydroxyl group at the C7 position of mitragynine, produced the most potent effect, suggesting that the opioid effect of Mitragyna speciosa is mostly based on the activity of 7-hydroxymitragynine (Horie et al., 2005).

7-Hydroxymitragynine induced a potent antinociceptive effect in mice, and its effect was more potent than those of morphine when subcutaneously or orally administered and mediated by the μ-opioid receptor mechanism (Matsumoto et al., 2004; Matsumoto et al., 2006). Furthermore, 7-hydroxymitragynine inhibited gastrointestinal transit less potently than morphine at each equi-antinociceptive dose (Matsumoto et al., 2006). The structural similarities between morphine and 7-hydroxymitragynine have been investigated using molecular modeling techniques (Matsumoto et al., 2005), but could not superimpose all three functional groups, i.e., a nitrogen atom, a benzene residue, and an oxygen atom on the benzene ring in the structures of morphine and 7-hydroxymitragynine. These functional groups have been considered to play an important role in producing analgesic activity (Dhawan et al., 1996).
A need has been recognized and solved by the present inventors for developing unique and potent analgesic compounds that can provide pain relief and/or prevention with reduced side effects.